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P4‐505: SIRT1 ENHANCES AUTOPHAGIC RESPONSE AND NON‐AMYLOIDOGENIC PROCESSING OF APP IN OLIGOMERIC Aβ 1‐42 INDUCED RAT MODEL FOR ALZHEIMER'S DISEASE
Author(s) -
Chennakesavan Karthick,
Swaminathan Jayachandran,
Muthuswamy Anusuyadevi
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.051
Subject(s) - autophagy , neurodegeneration , hippocampal formation , resveratrol , hippocampus , endocrinology , adam10 , atg5 , medicine , entorhinal cortex , epigenetics , biology , pharmacology , gene , disease , apoptosis , biochemistry , disintegrin , metalloproteinase , matrix metalloproteinase
Background: Epigenetic mechanism has been widely discussed in etiopathology ofmetabolic disorders likeDiabetes. However, epigenetics in neurodegeneration is least studied. SIRT1, a homeostatic regulator and widely known epigenetic factor seems to be suppressed in conditions like Alzheimer’s disease. Deficient SIRT1 is closely associated with Ab accumulation and disease progression that results in synaptic dysfunction. Therefore, the current study tends to observe the effect of Resveratrol (RSV)mediated SIRT1 activity on altered epigenetic regulation on major pathways like APP metabolism and autophagy gene response in oligomeric Ab (oAb142) induced rat model for AD. Methods: Oligomeric Ab1-42 (oAb142) was injected bilaterally (bregma: -4.0mm, mediolateral: 6 3.0mm and dorsoventral: -3.6mm) into the hippocampus of adult rats using stereotaxic surgery, following intraperitoneal administration of resveratrol (RSV), 30 mg/kg body weight for 14 days. The mRNA expression of Sirtuins (1-7) and autophagy regulated genes (ATG5, 6, 7, 12, 16L1), mTOR and BACE1 level were analysed using RT-PCR analysis. ADAM10, BACE1, PS1 & 2, GSK3b and SIRT1 levels were measured in hippocampal tissue of rat brain using Western blotting analysis. Results: Single Intra-hippocampal injection of oAb1-42 impaired the Sirt1, 4 and 7 mRNA levels and autophagy regulated genes with a simultaneous decrease in ADAM10 expression in hippocampus of adult rats. Further oAb142 increased the expression of BACE1 mRNA and protein levels, with increasing extracellular accumulation of Ab in hippocampus and entorhinal cortex. Resveratrol administration caused significant increase in autophagy related genes, include Atg5, 6 and 7 mRNA levels depicting positive epigenetic mechanism of SIRT1 in preventing Ab accumulation. Interestingly, SIRT1 activation increased a-secretase activity, decreasing BACE1 and GSK3b expression that facilitate non-amyloidogenic processing of APP. Conclusions: Present study concludes that RSV mediated SIRT1, facilitated autophagic response and provoked non-amyloidogenic processing of APP through epigenetic regulation.